This proposed training plan will provide high-quality professional development for the applicant through the pursuit of experiments designed to determine the impact of acute physical activity on mechanisms that mediate hippocampal plasticity and learning, with the goals of using exercise as a tool to understand and eventually apply these mechanisms to other therapeutic strategies to enhance brain health. Trafficking of AMPA-type glutamate receptors (AMPARs) to and from the synapse is essential for synaptic plasticity. Understanding the mediators of membrane insertion of AMPARs has been a focus of intense investigation in the search for mechanisms mediating long-term potentiation (LTP), a cellular model for learning and memory. Phosphorylation of the GluR1 subunit of the AMPAR at sites specific for membrane trafficking and synaptic plasticity can be induced in vivo by stimuli that cause physiological arousal and in vitro by hormones and growth factors that are upregulated following acute bouts of exercise. Indeed, short-term exercise training can improve hippocampal dependent learning and memory and lower the threshold for LTP, though the mechanisms mediating this effect are unknown. In contrast to chronic exercise, little is known about the molecular response to an acute bout of exercise. Traditionally, acute exercise studies have utilized exercise-based acclimation periods or multiple-day voluntary wheel running protocols, making the interpretation of an acute exercise effect difficult. Therefore, the overall goal of the present application, in combination with carefully integrated career development activities and mentors with expertise in neural plasticity and exercise physiology, is to describe the impact of acute bouts of exercise on hippocampal- dependent learning and memory, GluR1 phosphorylation, and other markers of hippocampal plasticity. Mice will be separated into non-exercise control, moderate-intensity, or high-intensity exercise groups and exposed to a single acute bout of treadmill exercise. Immediately following the exercise, the animals will be tested on a one-trial memory task or sacrificed for hippocampal biochemical and gene expression analysis. Using a noradrenergic specific neurotoxin and exogenous epinephrine, the role of central and peripheral catecholamine signaling and potential additive effects of exercise and catecholamines in exercise-induced plasticity will be determined. In the final set of experiments, animals will be provided access to a voluntary running wheel for 1 month prior to the acute bout of treadmill exercise to determine how prior exercise training modulates the response to an acute bout of exercise. Characterizing the molecular response to acute bouts of exercise is a unique and highly informative approach to understanding mechanisms that improve brain health and enhance neural plasticity. Identification of these mechanisms will have far broader implications than exercise alone, such as informing pharmaceutical research, school based learning programs, treatment of PTSD, depression, and anxiety disorders, and understanding abnormal brain physiology in aging and disease.